Both basic and clinical studies suggest that genetic as well as environmental factors play an important role in the regulation of the development of synaptic circuitry in the brain. And there is considerable basis for speculation that disturbances in synaptic circuitry, especially of the central catecholaminergic neurons, may play a role in the pathophysiology of schizophrenia and affective disturbances. In ongoing studies, we are examining the effects of ablation of cortical neurons in the fetal brain on the innervation of the cortex by noradrenergic and dopaminergic terminals. The lesions are made by treatment of the pregnant mother with a single injection of methylazoxymethanol acetate, a potent alkylating agent with a short half-life; this drug selectively kills cells that are actively dividing but spares postmitotic cells or quiescent cells in the GO phase. Results obtained thus far indicate that the noradrenergic neurons develop a quantitatively normal terminal arbor in the lesioned atrophic cortex; as a result, there is an increased density or relative hyperinnervation of the lesioned cerebral cortex as compared to the control. Preliminary studies suggest that the nigro-striatal dopaminergic pathway is also relatively insensitive to the loss of neurons in its postsynaptic areas of innervation. These studies indicate that central catecholaminergic neurons may not have rigidly determined postsynaptic sites of innervation but rather are capable of seeking alternative postsynaptic partners when the normal synaptic circuitry is disrupted. Future studies in the project will be directed at determining whether the increased density of innervation is functionally significant through defining receptor alterations and responsiveness. In addition, the effects of cortical lesions on the A-10 dopaminergic frontal cortical projection will be explored.